Sepsis syndrome arises from a systemic inflammatory response syndrome (SIRS) initiated by an infectious insult. Of approximately 751,000 cases of sepsis syndrome that occur annually in the United States, 35-45% of patients who experience this syndrome die (Angus et al., Crit. Care Med. 29(7):1303-1310 (2001); Crit. Care Med. 20(6):864-874 (1992)). While precise mechanisms leading to organ dysfunction mediated by SIRS and sepsis remain incompletely understood (Levy et al., Crit. Care Med. 31(4):1250-1256 (2003), Bone, Crit. Care Med. 24(1):163-172 (1996), Goldie et al., JAMA 274(2):172-177 (1995), Rangel-Frausto et al., JAMA 273(2):117-123 (1995), recent evidence suggests a novel role for lipid mediators (Alvarez and Ramos, Clin. Chem. 32(1 Pt 1):142-145 (1986), van Leeuwen et al., Crit. Care Med. 31(5):1359-1366 (2003), Fraunberger et al., Schok 10(5):359-363 (1998), Gordon et al., Crit. Care Med. 24(4):584-589 (1996)).
Lipid profile alterations have been reported in many acute inflammatory processes (Alvarez and Ramos, Clin. Chem. 32(1 Pt 1):142-145 (1986)). Recently, an inverse correlation was described between tumor-necrosis factor alpha (TNF α) and lipid components (van Leeuwen et al., Crit. Care Med. 31(5):1359-1366 (2003), Fraunberger et al., Schok 10(5):359-363 (1998), Gordon et al., Crit. Care Med. 24(4):584-589 (1996)). Apolipoprotein E (apoE protein; APOE gene) is a 34 kDa protein originally studied for its role in cholesterol metabolism. Independent of its role in cholesterol metabolism, apoE modulates innate and acquired immune responses in vitro and in vivo (Laskowitz et al., J. Lipid Res. 41(4):613-620 (2000)). ApoE deficient animals have impaired immunity after bacterial challenge, and they also have increased susceptibility to endotoxemia after intravenous lipopolysaccharide (LPS) administration (Roselaar and Daugherty, J. Lipid Res. 39(9):1740-1743 (1998), de Bont et al., J. Lipid Res. 40(4):680-685 (1999)). ApoE deficient animals also have been reported to have an increased systemic inflammatory response and higher mortality following LPS injection, and administration of exogenous apoE improved mortality by down regulating the inflammatory cascade (Van Ooosten et al., J. Biol. Chem. 276(12):8820-8824 (2001)).
There are three common human isoforms of apoE, designated E2, E3 and E4, encoded for by three alleles at the APOE locus on human chromosome 19 (Weisgraber, Adv. Protein Chem. 45:249-302 (1994)). These isoforms differ by single amino acid interchanges at residues 112 and 158: E3 (Cys112 Arg58); E4 (Arg112 Arg158); and E2 (Cys112 Cys158) (Weisgraber, Adv. Protein Chem. 45:249-302 (1994)). Isoform-specific differences in immune regulation have been described for apoE, and may play a pivotal role in mediating the CNS and systemic response to injury. For example, a recent preclinical study demonstrated that mice expressing the human APOE4 gene have enhanced systemic and CNS inflammatory responses following lipopolysaccharide (LPS) injection, as compared to their APOE3 counterparts (Curtiss and Edgington, J. Immunol. 126(4):1382-1386 (1981)). In addition, the apoE4 protein has been shown to be less effective than apoE3 or apoE2 at suppressing the activation of microglia in cell culture models of brain inflammation (Barger and Harmon, Nature 388(6645):878-881 (1997), Laskowitz et al., Exp. Neurol. 167(1):74-85 (2001)). Indeed the APOE4 allele has been associated with the early onset of Alzheimer's disease and poor prognosis in multiple sclerosis (Strittmatter and Roses, Annu. Rev. Neurosci. 19:53-77 (1996), Schmidt et al., Am. J Hum. Genet. 70(3):708-717 (2002)), as well as poor prognosis following traumatic brain injury, and with an increase in the systemic inflammatory response following cardiopulmonary bypass (Sorbi et al., Nat. Med. 1(9):852 (1995), Friedman et al., Neurology 52(2):244-248 (1999), Grocott et al., J. Thorac. Cardiovasc. Surg. 122(3):622-623 (2001)).
The present invention overcomes previous shortcomings in the art by providing methods of identifying individual having a reduced risk of sepsis.